title: Suppression of polyglutamine protein toxicity by co-expression of a heat-shock protein 40 and a heat-shock protein 110.
abstract: A network of heat-shock proteins mediates cellular protein homeostasis, and has a fundamental role in preventing aggregation-associated neurodegenerative diseases. In a Drosophila model of polyglutamine (polyQ) disease, the HSP40 family protein, DNAJ-1, is a superior suppressor of toxicity caused by the aggregation of polyQ containing proteins. Here, we demonstrate that one specific HSP110 protein, 70 kDa heat-shock cognate protein cb (HSC70cb), interacts physically and genetically with DNAJ-1 in vivo, and that HSC70cb is necessary for DNAJ-1 to suppress polyglutamine-induced cell death in Drosophila. Expression of HSC70cb together with DNAJ-1 significantly enhanced the suppressive effects of DNAJ-1 on polyQ-induced neurodegeneration, whereas expression of HSC70cb alone did not suppress neurodegeneration in Drosophila models of either general polyQ disease or Huntington's disease. Furthermore, expression of a human HSP40, DNAJB1, together with a human HSP110, APG-1, protected cells from polyQ-induced neural degeneration in flies, whereas expression of either component alone had little effect. Our data provide a functional link between HSP40 and HSP110 in suppressing the cytotoxicity of aggregation-prone proteins, and suggest that HSP40 and HSP110 function together in protein homeostasis control.
authors.affiliation: Division of Basic Sciences, National Institute of Biological Sciences, Beijing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Kuo
authors.forename: S
authors.initials: S
authors.lastname: Ren
authors.forename: U
authors.initials: U
authors.lastname: Lao
authors.forename: B A
authors.initials: BA
authors.lastname: Edgar
authors.forename: T
authors.initials: T
authors.lastname: Wang
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D050957:HSP110 Heat-Shock Proteins / Q000378:metabolism*; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism / Q000473:pathology; D047468:Immunoprecipitation; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000633:toxicity*; D011485:Protein Binding / Q000187:drug effects; D012160:Retina / Q000473:pathology / Q000648:ultrastructure
chemical_list: C586894:70 kDa heat-shock cognate protein cb, Drosophila; C494647:DNAJB1 protein, human; C494637:DnaJ-1 protein, Drosophila; D029721:Drosophila Proteins; D050957:HSP110 Heat-Shock Proteins; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; C490979:HSPA4L protein, human; D010455:Peptides; C097188:polyglutamine